- Structure guided design and synthesis of furyl thiazolidinedione derivatives as inhibitors of GLUT 1 and GLUT 4, and evaluation of their anti-leukemic potential
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Cancer cells increase their glucose uptake and glycolytic activity to meet the high energy requirements of proliferation. Glucose transporters (GLUTs), which facilitate the transport of glucose and related hexoses across the cell membrane, play a vital ro
- Aguilera, Renato J.,Choe, Jun-yong,Hess, Jessica D.,Iancu, Cristina V.,Macias, Lucasantiago Henze,Meyer-Almes, Franz-Josef,Mrowka, Piotr,Ramaa, C. S.,Tilekar, Kalpana,Upadhyay, Neha
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- New acetamide derivatives containing (ω-p-bromophenoxyalkyl)uracil moiety and their anticytomegalovirus activity
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New N-aryl-2-{3-[ω-(4-bromophenoxy)alkyl]-2,6-dioxo-3,6-dihydropyrimidin-1(2H)-yl}acetamides have been obtained from 1-[ω-(4-bromophenoxy)alkyl]uracil and 2-chloro-N-(4-phenoxyphenyl)acetamide derivatives. Investigation of their antiviral properties again
- Andrei, Graciela,Khandazhinskaya, Anastasia L.,Novikov, Mikhail S.,Paramonova, Maria P.,Snoeck, Robert
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p. 602 - 603
(2020/10/09)
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- COMPOSITONS AND METHODS FOR MODULATING UBA5
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Disclosed herein, inter alia, are compositions and methods useful for inhibiting ubiquitin-like modifier activating enzyme 5.
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-
Paragraph 0633; 0635; 0638; 0646
(2018/08/26)
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- COMPOSITIONS AND METHODS FOR MODULATING PPP2R1A
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Disclosed herein, inter alia, are compositions and methods useful for modulating PPP2R1 A and for the treatment of cancer.
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Paragraph 0599; 0600; 0607; 0622
(2018/08/26)
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- COMPOSITIONS AND METHODS FOR INHIBITING RETICULON 4
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Disclosed herein, inter alia, are compositions and methods useful for inhibiting reticulon 4(RTN4).
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-
Paragraph 0646; 0649
(2018/08/26)
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- Chemoproteomics-enabled covalent ligand screen reveals a cysteine hotspot in reticulon 4 that impairs ER morphology and cancer pathogenicity
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Chemical genetics has arisen as a powerful approach for identifying novel anti-cancer agents. However, a major bottleneck of this approach is identifying the targets of lead compounds that arise from screens. Here, we coupled the synthesis and screening of fragment-based cysteine-reactive covalent ligands with activity-based protein profiling (ABPP) chemoproteomic approaches to identify compounds that impair colorectal cancer pathogenicity and map the druggable hotspots targeted by these hits. Through this coupled approach, we discovered a cysteine-reactive acrylamide DKM 3-30 that significantly impaired colorectal cancer cell pathogenicity through targeting C1101 on reticulon 4 (RTN4). While little is known about the role of RTN4 in colorectal cancer, this protein has been established as a critical mediator of endoplasmic reticulum tubular network formation. We show here that covalent modification of C1101 on RTN4 by DKM 3-30 or genetic knockdown of RTN4 impairs endoplasmic reticulum and nuclear envelope morphology as well as colorectal cancer pathogenicity. We thus put forth RTN4 as a potential novel colorectal cancer therapeutic target and reveal a unique druggable hotspot within RTN4 that can be targeted by covalent ligands to impair colorectal cancer pathogenicity. Our results underscore the utility of coupling the screening of fragment-based covalent ligands with isoTOP-ABPP platforms for mining the proteome for novel druggable nodes that can be targeted for cancer therapy.
- Bateman,Nguyen,Roberts,Miyamoto,Ku,Huffman,Petri,Heslin,Contreras,Skibola,Olzmann,Nomura
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supporting information
p. 7234 - 7237
(2017/07/11)
-
- Synthesis, molecular docking and α-glucosidase inhibition of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides
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A novel series of 2-((5,6-diphenyl-1,2,4-triazin-3-yl)thio)-N-arylacetamides 5a–5q have been synthesized and evaluated for their α-glucosidase inhibitory activity. All newly synthesized compounds exhibited potent α-glucosidase inhibitory activity in the range of IC50?=?12.46?±?0.13–72.68?±?0.20?μM, when compared to the standard drug acarbose (IC50?=?817.38?±?6.27?μM). Among the series, compound 5j (12.46?±?0.13?μM) with strong electron-withdrawing nitro group on the arylacetamide moiety was identified as the most potent inhibitor of α-glucosidase. Molecular docking study was carried out to explore the binding interactions of these compounds with α-glucosidase. Our study identifies a novel series of potent α-glucosidase inhibitors for further investigation.
- Wang, Guangcheng,Li, Xin,Wang, Jing,Xie, Zhenzhen,Li, Luyao,Chen, Ming,Chen, Shan,Peng, Yaping
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p. 1115 - 1118
(2017/06/19)
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- Compound Combinations for Attenuation of Bacterial Virulence
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Methods for modulating quorum sensing in certain Gram-negative bacteria having multiple QS systems including Las, Rhl, and Pqs with associated receptors (LasR, RhlR and PqsR) which are modulated by small molecule modulators, particularly non-native modula
- -
-
Paragraph 0284; 0285
(2017/09/02)
-
- Discovery of potent nitrotriazole-based antitrypanosomal agents: In vitro and in vivo evaluation
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3-Nitro-1H-1,2,4-triazole- and 2-nitro-1H-imidazole-based amides with an aryloxy-phenyl core were synthesized and evaluated as antitrypanosomal agents. All 3-nitrotriazole-based derivatives were extremely potent anti-Trypanosoma cruzi agents at sub nM con
- Papadopoulou, Maria V.,Bloomer, William D.,Rosenzweig, Howard S.,O'Shea, Ivan P.,Wilkinson, Shane R.,Kaiser, Marcel,Chatelain, Eric,Ioset, Jean-Robert
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supporting information
p. 6467 - 6476
(2015/10/05)
-
- Toward the discovery of dual HCMV-VZV inhibitors: Synthesis, structure activity relationship analysis, and cytotoxicity studies of long chained 2-uracil-3-yl-N-(4-phenoxyphenyl)acetamides
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The need for novel therapeutic options to fight herpesvirus infections still persists. Herein we report the design, synthesis and antiviral evaluation of a new family of non-nucleoside antivirals, derived from 1-[ω-(4-bromophenoxy)alkyl]uracil derivatives - previously reported inhibitors of human cytomegalovirus (HCMV). Introduction of the N-(4-phenoxyphenyl)acetamide side chain at N3 increased their potency and widened activity spectrum. The most active compounds in the series exhibit submicromolar activity against different viral strains of HCMV and varicella zoster virus (VZV) replication in HEL cell cultures. Inactivity against other DNA and RNA viruses, including herpes simplex virus 1/2, points to a novel mechanism of antiviral action.
- Babkov, Denis A.,Khandazhinskaya, Anastasia L.,Chizhov, Alexander O.,Andrei, Graciela,Snoeck, Robert,Seley-Radtke, Katherine L.,Novikov, Mikhail S.
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p. 7035 - 7044
(2015/11/11)
-
- A three-component one-pot synthesis of 2-alkoxy-4-amino-N-arylthiazole-5- carboxamides
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A facile and efficient protocol was developed to access 2-alkoxy-4-amino-N-arylthiazole-5-carboxamides through a three-component one-pot reaction, which involved potassium methyl cyanimidodithiocarbonate, 2-halo-N-arylacetamides and alcohols. The easy availability and the broad structural diversity of substrates make the reaction useful for the construction of libraries in drug discovery.
- Zhao, Hai-Long,Zhou, Jie,Song, Hong-Rui,Xu, Bai-Ling
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supporting information
p. 411 - 414
(2014/03/21)
-
- COMPOUNDS USEFUL AS ANTIBIOTIC TOLERANCE INHIBITORS
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The disclosure provides compounds and pharmaceutical compositions of the compounds useful for treating chronic and acute bacterial infections. Certain of the compounds are compounds and salts of general Formula VIII Certain compounds of this disclosure are MvfR inhibitors. MvfR inhibitors reduce the formation of antibiotic tolerant bacterial strains and are useful for treating Gram-negative bacterial infections and reducing the virulence of Pseudomonas aeruginosa. Methods of treating bacterial infections in a patient, including Pseudomonas aeruginosa infections, are also provided by the disclosure.
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-
Page/Page column 28
(2014/11/13)
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- Discovery of novel N -phenylphenoxyacetamide derivatives as EthR inhibitors and ethionamide boosters by combining high-throughput screening and synthesis
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In this paper, we describe the screening of a 14640-compound library using a novel whole mycobacteria phenotypic assay to discover inhibitors of EthR, a transcriptional repressor implicated in the innate resistance of Mycobacterium tuberculosis to the second-line antituberculosis drug ethionamide. From this screening a new chemical family of EthR inhibitors bearing an N-phenylphenoxyacetamide motif was identified. The X-ray structure of the most potent compound crystallized with EthR inspired the synthesis of a 960-member focused library. These compounds were tested in vitro using a rapid thermal shift assay on EthR to accelerate the optimization. The best compounds were synthesized on a larger scale and confirmed as potent ethionamide boosters on M. tuberculosis-infected macrophages. Finally, the cocrystallization of the best optimized analogue with EthR revealed an unexpected reorientation of the ligand in the binding pocket.
- Flipo, Marion,Willand, Nicolas,Lecat-Guillet, Nathalie,Hounsou, Candide,Desroses, Matthieu,Leroux, Florence,Lens, Zoé,Villeret, Vincent,Wohlk?nig, Alexandre,Wintjens, René,Christophe, Thierry,Kyoung Jeon, Hee,Locht, Camille,Brodin, Priscille,Baulard, Alain R,Déprez, Benoit
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supporting information; experimental part
p. 6391 - 6402
(2012/10/07)
-
- Inhibition of dengue virus and west Nile virus proteases by click chemistry-derived benz[d]isothiazol-3(2H)-one derivatives
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Two click chemistry-derived focused libraries based on the benz[d]isothiazol-3(2H)-one scaffold were synthesized and screened against Dengue virus and West Nile virus NS2B-NS3 proteases. Several compounds (4l, 7j-n) displayed noteworthy inhibitory activity toward Dengue virus NS2B-NS3 protease in the absence and presence of added detergent. These compounds could potentially serve as a launching pad for a hit-to-lead optimization campaign.
- Tiew, Kok-Chuan,Dou, Dengfeng,Teramoto, Tadahisa,Lai, Huiguo,Alliston, Kevin R.,Lushington, Gerald H.,Padmanabhan,Groutas, William C.
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experimental part
p. 1213 - 1221
(2012/03/26)
-
- ANTIBIOTIC TOLERANCE INHIBITORS
-
The present disclosure relates to benzimidazole-benzamide derivatives, and the use thereof, e.g., to treat infections.
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-
Page/Page column 29
(2012/09/11)
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- Tri-substituted triazoles as potent non-nucleoside inhibitors of the HIV-1 reverse transcriptase
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A new series of 1,2,4-triazoles was synthesized and tested against several NNRTI-resistant HIV-1 isolates. Several of these compounds exhibited potent antiviral activities against efavirenz- and nevirapine-resistant viruses, containing K103N and/or Y181C mutations or Y188L mutation. Triazoles were first synthesized from commercially available substituted phenylthiosemicarbazides, then from isothiocyanates, and later by condensing the desired substituted anilines with thiosemicarbazones.
- De La Rosa, Martha,Kim, Hong Woo,Gunic, Esmir,Jenket, Cheryl,Boyle, Uyen,Koh, Yung-hyo,Korboukh, Ilia,Allan, Matthew,Zhang, Weijian,Chen, Huanming,Xu, Wen,Nilar, Shahul,Yao, Nanhua,Hamatake, Robert,Lang, Stanley A.,Hong, Zhi,Zhang, Zhijun,Girardet, Jean-Luc
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p. 4444 - 4449
(2007/10/03)
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- ACTIVE SUBSTANCE COMBINATION COMPRISING A COMPOUND WITH NPY RECEPTOR AFFINITY AND A COMPOUND WITH 5-HT6 RECEPTOR AFFINITY
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The present invention relates to an active substance combination comprising at least one compound with neuropeptide Y-receptor affinity and at least one compound with 5-HT6 receptor affinity, a medicament comprising said active substance combination, and
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-
Page/Page column 280
(2010/02/10)
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- Benzoxazinone-derived compounds, their preparation and use as medicaments
-
The present invention relates to Benzoxazinone-derived compounds of general formula (I), methods for their preparation, medicaments comprising these compounds as well as their use for the preparation of a medicament for the treatment of humans or animals.
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Page/Page column 17
(2008/06/13)
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- A one-pot synthesis of pyrido[2,3.b][1,4]oxazin-2-ones
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Pyrido[2,3-b][1,4]oxazin-2-ones are conveniently prepared in excellent yields by a one-pot annulation of N-substituted-2-chloroacetamides with 2-halo-3-hydroxypyridines with use of cesium carbonate in refluxing acetonitrile. The key transformation features a Smiles rearrangement of the initial O-alkylation product and subsequent cyclization.
- Cho, Su-Dong,Park, Yong-Dae,Kim, Jeum-Jong,Lee, Sang-Gyeong,Ma, Chen,Song, Sang-Yong,Joo, Woo-Hong,Falck,Shiro, Motoo,Shin, Dong-Soo,Yoon, Yong-Jin
-
p. 7918 - 7920
(2007/10/03)
-